Skeletal muscle is a highly specialized tissue composed of non-dividing, multinucleated muscle fibers that contract to generate force in a controlled and directed manner. Skeletal muscle is formed during embryogenesis from a subset of muscle precursor cells found in a region of the embryo known as the myotome. In addition to generating differentiated muscle fibers, these cells also give rise to specialized muscle-forming stem cells, known as satellite cells, which remain associated with muscle fibers and are responsible for muscle growth and repair throughout life (Gros et al., 2006; Seale et al., 2000). Injury-induced satellite cell proliferation both replenishes the satellite cell pool and produces differentiated myoblasts which fuse with existing myofibers and with one another to regenerate muscle tissue.
Satellite cells are defined anatomically by their localization beneath the basal lamina of muscle fibers (Mauro, 1961) and molecularly by their expression of the paired-box transcription factor Pax7 (Seale et al., 2000). In resting muscle, satellite cells are maintained in a largely dormant state, but in response to muscle damage, these cells become activated, an event marked by their upregulation of MyoD, and enter the cell cycle (Seale et al., 2000). Transplantation-based studies in animal models have demonstrated the utility of engrafted satellite cells for regenerating diseased muscle (Cerletti et al., 2008; Sherwood et al., 2004) and analyses of mouse and human muscles indicate that their loss during aging contributes to age-associated muscle weakness (Cerletti et al., 2012). Thus, muscle satellite cells are promising targets for cell therapies involving either cell replacement or activation of endogenous repair mechanisms. However, realization of this promise has been hindered by the paucity of satellite cells that can be isolated from adult skeletal muscle and a lack of methods to support their ex vivo expansion.
In contrast to satellite cells, embryonic stem cells (ESCs) and, more recently, iPSCs process boundless expansion potential in culture and are theoretically capable of generating an unlimited supply of differentiated cell types, including myogenic cells. Although some success has been achieved in directing the myogenic differentiation of ESCs/IPSCs, largely through genetic manipulation and cell sorting approaches (Barberi et al., 2007; Darabi et al., 2008; Mizuno et al., 2010; Zheng et al., 2006), the generation of well differentiated muscle cells from human or murine pluripotent cells has proved very challenging. Thus, to realize the promise of stem cell approaches or muscle biology and regeneration, it is essential to uncover the molecular pathways that regulate the myogenic specification of these cells, and to develop systems that enable their robust and selective differentiation in ex vivo systems.